Ranolazine
Ranolazine
Generic Name
Ranolazine
Mechanism
Ranolazine is a *late sodium current* blocker that reduces the intracellular sodium and calcium overload in myocardial cells.
• Inhibits the late Na⁺ current (I_Na,L) → ↓ Na⁺ → ↓ Ca²⁺ via the Na⁺/Ca²⁺ exchanger
• Lowers intracellular Ca²⁺ → ↓ diastolic tension and myocardial oxygen consumption
• Improves coronary perfusion and reduces ischemic contracture without significant negative inotropy or chronotropy
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Pharmacokinetics
- Administration: Oral tablets
- Bioavailability: ~70–80 % after repeated dosing (≈50 % with a single dose)
- T_max: 1–2 h post‑dose
- Protein binding: ~93 % (primarily to albumin)
- Metabolism: Hepatic, mainly by *CYP3A4* and *CYP2C9*
- Half‑life: 20–30 h (shorter in renal impairment)
- Elimination: 55 % renal, 45 % fecal (mainly metabolites)
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Indications
- Chronic stable angina pectoris that remains symptomatic despite optimal β‑blocker, ACEI/ARB, and calcium‑channel blocker therapy
- Add‑on therapy to nitrates, beta‑blockers, or CCBs when monotherapy is inadequate
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Contraindications
| Category | Key Points |
| Contraindicated | Severe hepatic impairment; prolonged QT syndrome; concomitant use with potent CYP3A4 inhibitors (e.g., ketoconazole, clarithromycin) |
| Caution | Advanced renal disease (eGFR <30 mL/min); concomitant use of medications that prolong QTc; patients with heart failure (risk of negative inotropy) |
| Warnings | Torsades de pointes; hepatotoxicity; significant QT prolongation (up to +10 ms) |
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Dosing
- Initiation: 500 mg PO BID (morning & evening)
- Titration: ↑ 500 mg/ BID every 2 weeks up to 1 000 mg BID (max 2 000 mg/day)
- Adjustments:
- Hepatic impairment: 250 mg BID or avoid in Child‑Pugh C
- Renal impairment: Reduce by 50 % if eGFR 30–50 mL/min; avoid if <30 mL/min
- Timing: With or without food; food increases C_max by ~30 %
- Duration: Long‑term chronic use; reassess every 6 months
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Adverse Effects
| Adverse Effect | Frequency |
| Nausea, diarrhea, constipation | 4–9 % |
| Headache, dizziness, fatigue | 3–6 % |
| Palpitations, tachycardia | <2 % |
| QTc prolongation | 10–15 % (≥10 ms increase) |
| Torsades de pointes | <1 % (risk higher with other QT‑prolonging drugs) |
| Elevated liver enzymes (AST/ALT) | <1 % (monitor) |
| Hypotension | <1 % (rare) |
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Monitoring
- Baseline: ECG (QTc), liver panel, renal function (eGFR), serum electrolytes
- Follow‑up:
- ECG at 4 weeks and after any dose escalation; repeat annually
- LFTs and renal panel every 3 months or sooner if symptoms arise
- Monitor for signs of torsades: palpitations, syncope, arrhythmia
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Clinical Pearls
1. Late‑sodium current blocker – unlike nitrates or β‑blockers, ranolazine does not cause vasodilation or β‑adrenergic blockade, making it ideal for patients with β‑blocker intolerance or refractory angina.
2. Improves diastolic function – by reducing intracellular Ca²⁺, it eases myocardial relaxation, beneficial in hypertrophic cardiomyopathy‑related angina.
3. Drug‑drug interactions – potent CYP3A4 inhibitors (ketoconazole, ritonavir) can raise ranolazine levels >2 ×; consider dose reduction or alternative therapy.
4. Combination with nitrates – safe and often synergistic, but avoid concurrent use with verapamil or diltiazem due to possible additive QT effects.
5. Renal dosing – adjust for eGFR 450 ms, consider alternative antianginals; if prolonged after initiation, taper or discontinue.
7. Patient education – counsel on reporting dizziness, palpitations, or syncope and on maintaining electrolytes (K⁺, Mg²⁺) to minimize torsades risk.
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